ABSTRACT Our laboratory has been focused on elucidating the molecular mechanisms that regulate progressive pulmonary fibrosis for over two decades. My contributions to the field of idiopathic pulmonary fibrosis research include using matrix hyaluronan as a model molecule to dissect the molecular mechanisms of progressive lung fibrosis. We have identified the role of hyaluronan fragments in regulating lung inflammation. We discovered that hyaluronan and hyaluronan receptors have roles in lung inflammation and in lung stem cell regeneration. We discovered an invasive fibroblast phenotype in mice as well as in idiopathic pulmonary fibrosis explants. We are generally credited with expanding the notion that matrix is more than just glue and has a dynamic role in regulating lung biology. One aspect of our work that I have been proud of is that we have published much of our science in non-subspecialty journals of reasonable impact. This suggests that although we study the lung, the concepts we have put forward have been deemed of interest to a broader audience. The goals of this R35 application are to identify the epithelial-mesenchymal interactions that lead to unremitting fibrosis. Specifically, we propose in this R35 to identify mechanisms for AEC2 failed regenerative capacity in mouse and man, to identify mechanisms for mesenchymal expansion in mice with impaired AEC2 renewal capacity, to identify the mechanisms by which beta-arrestin1 and CD44 regulate the invasive fibroblast phenotype, and to identify mechanisms by which the invasive fibroblast impairs AEC2 cell renewal. Augmenting scientific knowledge in understanding the underlying mechanisms and the mode of actions of these interactions in lung fibrosis could significantly aid therapeutic development for patients with progressive pulmonary fibrosis. My belief is that we need a drug that promotes alveolar progenitor cells renewal and a drug that targets pathogenic fibroblasts such as invasive fibroblasts. The studies that we propose in this R35 application may suggest new leads for therapeutic intervention we are not yet aware of and we want to have the freedom to pursue them. Furthermore, the benefit of longer-term funding of this award allows me to train the next generation of scientists as I have done during my time at Duke University as well as currently here at Cedars.